Long-lived antibody secreting cells (LLASCs) are critical immune effector cells constitutively secreting high affinity antibody providing prophylaxis against infections. In contrast to live attenuated viruses which can provide lifelong immunity, protein-based vaccines are known to poorly induce LLASCs, often requiring multiple boosting to generate sufficient antibody titer. The factors that control LLASC production are poorly understood, but are critically important for all humoral-based vaccines. Survival of LLASCs is chiefly mediated by soluble cytokines, such as APRIL in the BM, and IL-6 in secondary lymphoid tissues. After immunization, antibody secreting cells (ASCs) express variable levels of CD138, and its function was unclear, since it can bind 100+ proteins, and CD138-/- have no overt phenotype. However, we have recently published a study that finally details a direct role for CD138 for potent antibody responses, by controlling ASC maturation and survival after immunization. LLASCs express the highest level of CD138 among all cells, in comparison to newly minted ASCs, which express intermediate levels of CD138. We proposed that high expression of CD138 provides LLASCs with higher binding and accumulation of IL-6 and APRIL, which are limiting, leading to a competitive advantage over new ASCs for survival. In Aim 1, we will test this competition model in this grant, which can explain poor vaccine responses as well as how LLASCs are maintained over time and repeated immune responses. In Aim 2 we will explore ways to increase CD138 after vaccination to enhance ASC survival and long term immunity. In Aims 3 & 4, we will explore CD138 function in pathological conditions.